Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease.

Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310(5748):679-83.

Dietary restriction (DR) extends life span and improves glucose metabolism in mammals. Recent studies have shown that DR stimulates the production of brain-derived neurotrophic factor (BDNF) in brain cells, which may mediate neuroprotective and neurogenic actions of DR. Other studies have suggested a role for central BDNF signaling in the regulation of glucose metabolism and body weight. BDNF heterozygous knockout (BDNF+/-) mice are obese and exhibit features of insulin resistance. We now report that an intermittent fasting DR regimen reverses several abnormal phenotypes of BDNF(+/-) mice including obesity, hyperphagia, and increased locomotor activity. DR increases BDNF levels in the brains of BDNF(+/-) mice to the level of wild-type mice fed ad libitum. BDNF(+/-) mice exhibit an insulin-resistance syndrome phenotype characterized by elevated levels of circulating glucose, insulin, and leptin; DR reduces levels of each of these three factors. DR normalizes blood glucose responses in glucose tolerance and insulin tolerance tests in the BDNF(+/-) mice. These findings suggest that BDNF is a major regulator of energy metabolism and that beneficial effects of DR on glucose metabolism are mediated, in part, by BDNF signaling. Dietary and pharmacological manipulations of BDNF signaling may prove useful in the prevention and treatment of obesity and insulin resistance syndrome-related diseases.

Duan W, Guo Z, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology. 2003;144(6):2446-53.

Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFR?) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFR? and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFR? expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor ?, acrp30, adipocyte-expressed STAT proteins, or C/EBP?. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFR? receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene expression, and the specific receptor for this cytokine is induced in rodent models of obesity/type II diabetes. Ciliary neurotrophic factor (CNTF)1 was originally characterized as a trophic factor that supports the survival of embryonic chick ciliary ganglion neurons in vitro (1, 2). However, subsequent cloning and sequencing of CNTF revealed that it is unrelated to neurotrophins but is a member of the gp130 cytokine family along with interleukin-6, interleukin-11, LIF, OSM, leptin and CT-1 (3-5). The actions of CNTF are mediated, in part, by a CNTF-specific receptor (CNTFR?) that has homology to the interleukin-6R? (6). Upon translation, the C terminus of CNTFR? is cleaved. Mature CNTFR? has no transmembrane or cytosolic domains and is found on the outer surface of the cell membrane where it is attached by a glycosylphosphatidylinositol linkage sensitive to phosphatidylinositol-phospholipase C treatment (7). Initially, CNTFR? was described as being distributed predominantly within neural tissues (7) but has since been reported in skeletal muscle, adrenal gland, sciatic nerve, skin, kidney, and testes (8). CNTFR? can be cleaved from the cell surface and exist and act in a soluble form. The soluble CNTFR? has been detected in the serum and the cerebrospinal fluid and has been shown to initiate signaling in cells not responsive to CNTF alone (6, 9). Mice lacking CNTF develop normally and appear to have no visible defects well into adulthood, when they develop minor loss of motor neurons (10). However, mice lacking CNTFR? tend to have severe motor neuron defects and die perinatally because they fail to initiate feeding behaviors (11). CNTF signaling is initiated when CNTF binds CNTFR?, either in its soluble or membrane-bound form (12). Once a CNTF·CNTFR? complex is formed, two of these heterodimers come together and recruit a gp130 transducer protein, followed by a subsequent recruitment of LIFR protein. The resulting receptor complex is a hexamer of CNTF, CNTFR?, gp130, and LIFR in a 2:2:1:1 ratio, respectively (13). Within this complex, CNTF and CNTFR? make direct contacts with all the complex components (7, 12). CNTF·CNTFR? is considered to be a low affinity binding complex until further bound to gp130 and LIFR (14). Aside from this hexameric, high affinity binding complex, CNTF can bind its receptors and can induce signaling in the absence of CNTFR?, solely by binding to a gp130:LIFR dimeric receptor (15, 16). Although CNTF was first identified as a trophic factor in the ciliary ganglion, it was later found to act on other motor neuron populations (17). Hence, it was evaluated as a therapeutic tool in patients suffering from motor neuron diseases (18). Interestingly, during these trials, CNTF administration resulted in unexpected weight loss (19). Additional studies showed that, like leptin, CNTF can activate the same signaling molecules and that CNTFR? is co-localized with ObR in the hypothalamic nuclei involved in the regulation of feeding (20). CNTF can also cross the blood-brain barrier in a manner similar to leptin (21). CNTF treatment of leptin-deficient ob/ob mice was found to reduce adiposity, hyperphagia, and hyperinsulinemia associated with this genotype. Leptin administration had the same effect in these animals. However, unlike leptin, CNTF also corrected obesity-related phenotypes in leptin-resistant, ObR-deficient, db/db mice and in mice with diet-induced obesity that are partially resistant to leptin (22). CNTF and its synthetic analog, Axokine, have also been found to suppress NPY gene expression (23) and pCREB in the feeding-relevant brain sites (22). The weight loss caused by CNTF administration is due to the preferential loss of fat (24). It is believed to occur by resetting the hypothalamic weight set point, such that cessation of CNTF treatment does not result in overeating and rebound weight gain (22). Unlike cachectic cytokines, the appetite diminution during CNTF treatment does not appear to be due to stress, inflammatory responses, nausea, or conditioned taste aversion but is possibly due to the modification of NPYergic signaling (22, 25). In this study, we examined the regulation and activation of STATs and proteins by CNTF in adipocytes. The objective of this project was to determine whether CNTF, a cytokine known to result in weight loss, could have effects on peripheral tissues such as white adipose tissue. Our results clearly demonstrate that two of the three CNTF receptors are down-regulated during the adipogenesis of 3T3-L1 cells. However, CNTF administration results in the activation of STAT 3 in both cultured 3T3-L1 adipocytes and in rodent adipose tissue. Also this study provides the first evidence that CNTFR? is expressed in adipose tissue and that the expression of this receptor is regulated in four rodent models of obesity/type II diabetes. We also observed that CNTF treatment did not effect the expression of key adipogenic transcription factors such as PPAR? and C/EBP? but did result in a decrease of fatty-acid synthase (FAS) expression. Also, unlike other cachectic cytokines such as tumor necrosis factor-?, chronic CNTF treatment did not result in the development of insulin resistance in cultured adipocytes. Moreover, acute CNTF administration resulted in increased GLUT4 expression, whereas chronic CNTF treatment resulted in a substantial increase in IRS-1 expression. Also, acute CNTF treatment resulted in an increase in insulin-induced IRS-1 and Akt activation. In summary, the results of this study demonstrate that both cultured and native adipocytes, as well as skeletal muscle, are responsive to CNTF and that this cytokine may act as an insulin-sensitizer in cultured adipocytes. These studies support our hypothesis that the ability of CNTF to result in weight loss is not solely mediated by the central nervous system.

Zvonic S, Cornelius P, Stewart WC, Mynatt RL, Stephens JM. The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J Biol Chem. 2003;278(4):2228-35.

Unlike most other classes of receptors, where the cytoplasmic domain is necessary for signal transduction, receptors for IL-6 and other related cytokines signal solely by virtue of their ability to form a larger receptor complex with a common subunit, the transmembrane glycoprotein gp130 (1). For instance, binding of IL-6 to IL-6Rα, the α subunit of the functional receptor, triggers the association of IL-6Rα with gp130 (1, 2). Indeed, even a soluble form of IL-6Rα, entirely lacking the intracellular region of the protein, can bind to its ligand and to surface-expressed gp130, producing a normal IL-6 signal (1). The ligands of these various receptors are therefore referred to as the gp130 cytokine receptor family. As summarized in Figure ?Figure1,1, gp130 functions as a common cytokine signal transducer for IL-6, leukemia inhibitory factor (LIF), IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotropin-1 (CT-1), all of which bind specific receptors (their α subunits) but use the gp130 protein as the initial cellular signal transducer (2, 3). Because of this broad physiological role, the term gp130 is commonly used, in addition to its official human genome organization (HUGO) designation as the IL-6 signal transducer, or IL6ST.

Schematic model of the IL-6/gp130 receptor system. The specific cytokine-binding subunits and gp130 belong to a cytokine receptor superfamily characterized by four positionally conserved cysteine residues and a WSXWS motif. Functional receptor complexes ...

The human gp130 consists of an extracellular domain of 597 amino acids, with a single transmembrane domain of 22 amino acids, and a cytoplasmic domain of 277 amino acids. As with other hemopoietic cytokine receptors, gp130 contains a cytokine receptor homology region that includes fibronectin type III domains as well as four positionally conserved cysteine residues and a WSXWS motif (1, 3) (Figure ?(Figure1).1). While the expression of the gp130 cDNA alone does not confer the binding of IL-6 or the other family cytokines, gp130 and IL-6Ra together form a high-affinity IL-6 binding site.

In the mouse, gp130 is ubiquitously expressed in adult organs, as well as in embryonic stem cells and in embryos as early as day 6 of gestation (3). Expression of gp130 therefore does not parallel that of the α subunit of any of the receptors of the cytokine family, nor of any specific cytokine of the IL-6 family. These factors show some functional redundancy in the immune, hematopoietic, nervous, and neuro-endocrine systems. For example, macrophage differentiation, expression of acute-phase proteins by hepatocytes, and neuronal survival and differentiation can all be induced by multiple gp130 cytokines. Conversely, as is extensively reviewed in refs. 3–5, these cytokines also exhibit specific biological activities. Considering that gp130 is ubiquitously expressed, the time and place at which gp130 functions in vivo appears to be determined by spatially and temporally regulated expression of specific cytokine-binding receptor chains or of the cytokines themselves. In addition, soluble gp130, probably translated from an alternative spliced mRNA, can neutralize receptor signaling complexes, thereby acting as an antagonist (6). Below, I discuss the regulation of cytokine and cytokine receptor function in the pituitary gland and its importance for neuro-endocrine–stress responses.

Arzt E. gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine-neuro-endocrine pathways. J Clin Invest. 2001;108(12):1729-33.